Cherkesova Tatiana S, Hargrove Tatiana Y, Vanrell M Cristina, Ges Igor, Usanov Sergey A, Romano Patricia S, Lepesheva Galina I
Institute of Bioorganic Chemistry National Academy of Sciences of Belarus, Minsk 220141, Belarus.
Department of Biochemistry School of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
FEBS Lett. 2014 Nov 3;588(21):3878-85. doi: 10.1016/j.febslet.2014.08.030. Epub 2014 Sep 12.
CYP51 (sterol 14α-demethylase) is an efficient target for clinical and agricultural antifungals and an emerging target for treatment of Chagas disease, the infection that is caused by multiple strains of a protozoan pathogen Trypanosoma cruzi. Here, we analyze CYP51A from the Y strain T. cruzi. In this protein, proline 355, a residue highly conserved across the CYP51 family, is replaced with serine. The purified enzyme retains its catalytic activity, yet has been found less susceptible to inhibition. These biochemical data are consistent with cellular experiments, both in insect and human stages of the pathogen. Comparative structural analysis of CYP51 complexes with VNI and two derivatives suggests that broad-spectrum CYP51 inhibitors are likely to be preferable as antichagasic drug candidates.
细胞色素P450 51（甾醇14α-脱甲基酶）是临床和农业用抗真菌药物的有效靶点，也是治疗恰加斯病的新兴靶点，恰加斯病是由原生动物病原体克氏锥虫的多种菌株引起的感染。在此，我们分析了克氏锥虫Y株的细胞色素P450 51A。在这种蛋白质中，脯氨酸355（细胞色素P450 51家族中高度保守的一个残基）被丝氨酸取代。纯化后的酶保留了其催化活性，但已发现其对抑制作用的敏感性较低。这些生化数据与病原体在昆虫和人类阶段的细胞实验结果一致。对细胞色素P450 51与VNI及其两种衍生物形成的复合物进行的比较结构分析表明，广谱细胞色素P450 51抑制剂可能更适合作为抗恰加斯病药物候选物。
